HIV-1 vaccine induced immune responses have been relatively weak and of insufficient breadth to expect protection from infection. Likewise in the macaque HIV-1 vaccine model sterilizing immunity to SIV has been difficult to achieve. Novel approaches to immunization may be needed to induce protective immunity. One novel approach, proposed here, is to expose the host to virulent virus during antiviral prophylaxis given to prevent chronic infection. The administration of reverse transcriptase inhibitors could provide prophylaxis from chronic infection while allowing an modicum of infection which theoretically may be sufficient to produce protective immunity. Preliminary studies indicate that macaques successfully prophylaxed from SIV infection by (R)-9-(2-Phosphonylmethoxypropyl) adenine (PMPA) are protected from chronic infection or disease when subsequently challenged intravenously with SIV. These findings imply that protective immunity may indeed be induced by an infection limited by a reverse transcriptase inhibitor. We propose to determine the efficacy of PMPA in the prophylaxis of Macaca nemestrina from SIV infection following intravaginal exposures. Once prophylactic therapy is discontinued, we will determine if macaques are protected from infection or disease when challenged intravaginally with the same or different variants of SIV. Lastly, we will cryopreserve specimens to allow the evaluation of SIV specific cytotoxic T lymphocytes(CTLs) and neutralizing antibodies in the blood and genital secretions if effective prophylaxis and resistance to infection upon viral challenge are achieved. These studies will help evaluate whether resistance to lentiviruses can be induced by viral exposure during prophylaxis with reverse transcriptase inhibitors. The results of these studies should be applicable to the development of novel approaches to HIV-1 immunization.